CROSS LINKED OR BRANCHED POLYANHYDRIDES/COIMIDES AND PEPTIDE/PROTEIN RELEASE

交联或支化聚酐/酰亚胺和肽/蛋白质释放

• 批准号: 6311584
• 负责人: CARLOS A RAMFREZ
• 金额: $ 5.66万
• 依托单位: UNIVERSITY OF PUERTO RICO MAYAGUEZ
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6311584
• 关键词: aminoacid; artificial endocrine pancreas; artificial immunosuppression; biomaterial compatibility; biomaterial development /preparation; biomaterial evaluation; crosslink; cyclosporines; diabetes mellitus therapy; drug vehicle; laboratory rat; peptide chemical synthesis; polymers; proteolysis; radioimmunoassay; slow release drug

Over the last three decades, controlled drug release technology has attracted researchers around the world because it has proven to be an efficient means of administering bioactive agents to patients suffering from a variety of diseases. With genetic engineering products becoming increasingly available, controlled drug release systems have attained a new level of interest due to their high health and economic potential. Of the various modalities known to release drugs modalities known to release drugs at predictable rates, the erodible polymeric systems stand out because they do not have to be removed once implanted and many biocompatible polymers are known. Among the erodible systems, polyanhydrides have been studied extensively in controlled drug release applications to the point where polymer-drug matrices are now available for treating human brain tumors. However, most polyanhydrides are linear. Their backbone cleavage generally leads to the formation of "internal" erosion fronts with variable drug release rates, and their use in humans is limited to short-term (one to two months) applications. The goal of this project is to develop a monolith-type, polymer -drug matrix based on cross-linked or branched, amino acid-containing polyanhydrides capable of releasing peptides and proteins at predictable rates for months and even years after implantation in animals and humans. The underlying hypothesis is that these new polyanhydrides can be made to degrade at the surface by altering their chemical structure or the matrix formulation procedure. The specific aims are: 1) to synthesize and characterize cross-linked or branched poly(anhydride-co- imides) based on an amino acid-containing pre-polymer and a pre-polymer of a space molecule such as sebacic acid, glycolic acid, or L-lactic acid; 2) to formulate polymer-drug matrices based on the polymers synthesized and either porcine insulin or cyclosporin A as test proteins: 3) to incubate these matrices in aqueous media and determine the polymer degradation/drug release rates: 4) to determine the activity of the test proteins throughout the matrix formulation and incubation procedures; 5) to perform extensive mechanical tests on the polymer-drug matrices to assess their usefulness in vivo; and 6) to implant the polymer-drug matrices in diabetic (insulin-loaded matrices) and normal (cyclosporin A-loaded matrices) rates to determine the polymer degradation and drug release rates. The methods proposed include polymer synthesis and characterization using various chromatographic and spectrophotometric techniques; mechanical testing of freshly prepared and degraded polymer-drug matrices; activity testing of the entrapped peptides and protein using enzymatic and radioimmunoassay techniques; and in vivo implantation and follow-up of the polymer-insulin and polymer-cyclosporin A matrices in rats. The integrated approach involving fundamental polymer chemistry, as well as in vitro and in vivo testing, will lead to a more rational design of these polyanhydride-dug matrices and shed light on their potential use in long-term therapies for diabetes and immunosuppression.

在过去的三十年中，控释药物技术吸引了世界各地的研究人员，因为它已被证明是向患有多种疾病的患者施用生物活性剂的有效方法。随着基因工程产品的日益普及，受控药物释放系统因其较高的健康和经济潜力而受到了新的关注。在已知以可预测速率释放药物的各种已知释放药物模式中，可溶蚀聚合物系统脱颖而出，因为它们一旦植入就不必移除，并且许多生物相容性聚合物是已知的。在可侵蚀系统中，聚酸酐在受控药物释放应用中已得到广泛研究，目前聚合物药物基质可用于治疗人脑肿瘤。然而，大多数聚酐是线性的。它们的主链裂解通常会导致药物释放速率可变的“内部”侵蚀前沿的形成，并且它们在人类中的使用仅限于短期（一到两个月）应用。该项目的目标是开发一种基于交联或支链、含氨基酸聚酸酐的整体式聚合物药物基质，能够在植入动物和人类后数月甚至数年以可预测的速率释放肽和蛋白质。基本假设是，这些新的聚酸酐可以通过改变其化学结构或基质配制程序而在表面降解。具体目标是：1）基于含氨基酸预聚物和空间分子预聚物（如癸二酸、乙醇酸）的交联或支化聚（酸酐-酰亚胺）的合成和表征，或L-乳酸； 2) 基于合成的聚合物和猪胰岛素或环孢菌素 A 作为测试蛋白配制聚合物-药物基质： 3) 在水介质中孵育这些基质并测定聚合物降解/药物释放速率： 4) 测定聚合物的活性整个基质配制和孵育过程中的测试蛋白质； 5) 对聚合物-药物基质进行广泛的机械测试，以评估其在体内的有效性； 6) 将聚合物-药物基质植入糖尿病患者（装载胰岛素的基质）和正常人（装载环孢菌素A的基质）中，以确定聚合物的降解和药物释放速率。提出的方法包括使用各种色谱和分光光度技术进行聚合物合成和表征；新制备和降解的聚合物药物基质的机械测试；使用酶法和放射免疫分析技术对包埋的肽和蛋白质进行活性测试；以及聚合物-胰岛素和聚合物-环孢素A基质在大鼠体内的植入和随访。涉及基础聚合物化学以及体外和体内测试的综合方法将导致对这些聚酸酐挖掘基质进行更合理的设计，并揭示它们在糖尿病和免疫抑制的长期治疗中的潜在用途。